Retinoids are a class of compounds structurally related to vitamin A, comprising natural and synthetic compounds. Retinoids have been found to be clinically useful in the treatment of dermatological and oncological diseases.
Retinoids with retinoid receptor agonistic activity have been shown to be active not only in model systems for the treatment of dermatological and oncological diseases but also in models for the treatment of T-helper cell type 1 (Th1)-mediated immune diseases. Retinoids with retinoid receptor agonistic activity are active in the treatment of adjuvant arthritis [Brinckerhoffet al., Science 221, 756-758 (1983)] and experimental allergic encephalomyelitis [Massacesi et al., J. Clin. Invest. 88, 1331-1337 (1991); Racke et al., J. Immunol. 154, 450-458 (1995)], animal models for rheumatoid arthritis and multiple sclerosis, respectively. Both diseases are considered to belong to Th1-mediated, immune diseases.
Experimentally, retinoids with retinoid receptor antagonistic activity (retinoid antagonists) are effective in counteracting many properties of retinoids with retinoid receptor agonistic activity (retinoid agonists) such as inhibition of cell proliferation, induction of cell differentiation, induction of apoptosis and inhibition of angiogenesis [Bollag et al., Int. J. Cancer 70, 470-472 (1997)]. Retinoid antagonists are also suppressing toxic side effects of retinoid agonists such as the signs and symptoms of the hypervitaminosis A syndrome and teratogenesis [Standeven et al., Toxicol. Appl. Pharmacol. 138, 169-175 (1996); Eckhardt and Schmitt, Toxicol. Letters 70, 299-308 (1994)]. Therefore, they may be useful clinically in preventing or treating adverse events caused by retinoid agonists.
Retinoid antagonists have been proposed for clinical use in prevention and therapy of retinoid-induced toxicity and side effects, particularly of the so-called hypervitaminosis A syndrome. Retinoid antagonists have also been proposed to be used in combination with retinoid receptor agonists or other nuclear receptor agonists for prevention and treatment of preneoplastic or neoplastic lesions, vitreo-retinopathy and retinal detachment. In addition, retinoid antagonists have been proposed for use as single agents, based on their anti-proliferative effect, for treatment of certain neoplasms insensitive to retinoid receptor agonists [WO 97/09297].